ORCID Profile
0000-0002-6617-4359
Current Organisation
Deakin University
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Publisher: Cambridge University Press (CUP)
Date: 19-11-2010
Publisher: Wiley
Date: 03-03-2022
DOI: 10.1111/DOM.14669
Abstract: To investigate the effects of mitochondrial-targeted antioxidants (mitoAOXs) on glycaemic control, cardiovascular health, and oxidative stress outcomes in humans. Randomized controlled trials investigating mitoAOX interventions in humans were searched for in databases (MEDLINE-PubMed, Scopus, EMBASE and Cochrane Library) and clinical trial registries up to 10 June 2021. The Cochrane Collaboration's tool for assessing risk of bias and Grading of Recommendations, Assessment, Development and Evaluations were used to assess trial quality and evidence certainty, respectively. Nineteen studies (n = 884 participants) using mitoAOXs (including Elamipretide, MitoQ and MitoTEMPO) were included in the systematic review. There were limited studies investigating the effects of mitoAOXs on glycaemic control and outcomes and population groups in studies focusing on cardiovascular health were erse. MitoAOXs significantly improved brachial flow-mediated dilation (n = 3 trials standardized mean difference: 1.19, 95% CI: 0.28, 2.16 I While short-term studies indicate that mitoAOXs are generally well tolerated, there is currently limited evidence to support the use of mitoAOXs in the management of glycaemic control and cardiovascular health. Review findings suggest that future research should focus on the effects of mitoAOXs on glycaemic control and endothelial function in target clinical population groups.
Publisher: Cambridge University Press (CUP)
Date: 09-10-2014
DOI: 10.1017/S2040174414000452
Abstract: The importance of skeletal muscle for metabolic health and obesity prevention is gradually gaining recognition. As a result, interventions are being developed to increase or maintain muscle mass and metabolic function in adult and elderly populations. These interventions include exercise, hormonal and nutritional therapies. Nonetheless, growing evidence suggests that maternal malnutrition and obesity during pregnancy and lactation impede skeletal muscle development and growth in the offspring, with long-term functional consequences lasting into adult life. Here we review the role of skeletal muscle in health and obesity, providing an insight into how this tissue develops and discuss evidence that maternal obesity affects its development, growth and function into adult life. Such evidence warrants the need to develop early life interventions to optimise skeletal muscle development and growth in the offspring and thereby maximise metabolic health into adult life.
Publisher: Cold Spring Harbor Laboratory
Date: 28-04-2022
DOI: 10.1101/2022.04.27.489477
Abstract: Mitochondria are central to cellular function, particularly in metabolically active tissues such as skeletal muscle. Non-coding RNAs (ncRNAs) typically localise within the nucleus and cytosol but may also translocate to subcellular compartments such as mitochondria. We aimed to investigate the nuclear-encoded ncRNAs that localise within the mitochondria of skeletal muscle cells and tissue. Intact mitochondria were isolated via immunoprecipitation and an enzymatic digestion approach was optimised to remove transcripts located exterior to mitochondria, making it amenable for high-throughput transcriptomic sequencing. Small-RNA sequencing libraries were successfully constructed from as little as 1.8ng mitochondrial RNA input. Small-RNA and whole transcriptome sequencing of mitochondria reveals the enrichment of over 200 miRNAs and 200 lncRNAs that have not previously been observed within skeletal muscle mitochondria. In summary, we describe a novel, powerful sequencing approach applicable to animal and human tissues and cells that reveals the unexpected ersity of nuclear-encoded ncRNA transcripts localised within skeletal muscle mitochondria.
Publisher: Wiley
Date: 27-07-2020
DOI: 10.1113/JP277619
Abstract: AMP‐activated protein kinase (AMPK) is considered a major regulator of skeletal muscle metabolism during exercise. However, we previously showed that, although AMPK activity increases by 8–10‐fold during ∼120 min of exercise at ∼65% in untrained in iduals, there is no increase in these in iduals after only 10 days of exercise training (longitudinal study). In a cross‐sectional study, we show that there is also a lack of activation of skeletal muscle AMPK during 120 min of cycling exercise at 65% in endurance‐trained in iduals. These findings indicate that AMPK is not an important regulator of exercise metabolism during 120 min of exercise at 65% in endurance trained men. It is important that more energy is directed towards examining other potential regulators of exercise metabolism. AMP‐activated protein kinase (AMPK) is considered a major regulator of skeletal muscle metabolism during exercise. Indeed, AMPK is activated during exercise and activation of AMPK by 5‐aminoimidazole‐4‐carboxyamide‐ribonucleoside (AICAR) increases skeletal muscle glucose uptake and fat oxidation. However, we have previously shown that, although AMPK activity increases by 8–10‐fold during ∼120 min of exercise at ∼65% in untrained in iduals, there is no increase in these in iduals after only 10 days of exercise training (longitudinal study). In a cross‐sectional study, we examined whether there is also a lack of activation of skeletal muscle AMPK during 120 min of cycling exercise at 65% in endurance‐trained in iduals. Eleven untrained (UT = 37.9 ± 5.6 ml.kg −1 min −1 ) and seven endurance trained (ET = 61.8 ± 2.2 ml.kg −1 min −1 ) males completed 120 min of cycling exercise at 66 ± 4% (UT: 100 ± 21 W ET: 190 ± 15 W). Muscle biopsies were obtained at rest and following 30 and 120 min of exercise. Muscle glycogen was significantly ( P 0.05) higher before exercise in ET and decreased similarly during exercise in the ET and UT in iduals. Exercise significantly increased calculated skeletal muscle free AMP content and more so in the UT in iduals. Exercise significantly ( P 0.05) increased skeletal muscle AMPK α2 activity (4‐fold), AMPK αThr 172 phosphorylation (2‐fold) and ACCβ Ser 222 phosphorylation (2‐fold) in the UT in iduals but not in the ET in iduals. These findings indicate that AMPK is not an important regulator of exercise metabolism during 120 min of exercise at 65% in endurance trained men.
Publisher: Wiley
Date: 14-11-2007
Publisher: Wiley
Date: 02-12-2018
DOI: 10.1111/DOM.13571
Abstract: The primary aim of this study was to investigate whether ascorbic acid (AA) supplementation improves postprandial glucose responses under free-living conditions in in iduals with type 2 diabetes. A secondary aim was to investigate the effect of AA supplementation on blood pressure. A total of 31 in iduals with type 2 diabetes (26 males and 5 females aged 61.8 ± 6.8 years duration of diabetes, 5.6 ± 4.6 years HbA1c, 7.6% ± 0.7% [mean ± SD]) were enrolled in a randomized cross-over study involving 4 months of supplementation with oral AA (2 × 500 mg/d) or placebo. Participants wore continuous glucose monitors for 48 hours and consumed standardized meals pre- and post-supplementation. Measurements included postprandial glucose incremental areas under the curve (iAUC), duration of day in hyper- and hypo-glycaemia status, average 24-hour and daily postprandial glucose concentrations, HbA1c, insulin, blood pressure (BP) and oxidative stress (F Following AA supplementation, significant decreases were observed in daily postprandial glucose iAUC (-36%), in duration of day with hyperglycaemia (-2.8 h/d) and postprandial hyperglycaemia (-1.7 h/d), in average 24-hour glucose (-0.8 mmol/L) and daily postprandial glucose (-1.1 mmol/L) concentrations, in systolic (-7 mm Hg) and diastolic (-5 mm Hg) blood pressures and in a specific fraction of free plasma F In iduals with type 2 diabetes experienced improved postprandial and 24-hour glycaemia and decreased BP after 4 months of AA supplementation as compared to placebo. These findings offer evidence for the proposed use of AA as an adjunct therapy to improve glycaemic and BP control in in iduals with type 2 diabetes.
Publisher: American Physiological Society
Date: 15-05-2012
DOI: 10.1152/AJPENDO.00583.2011
Abstract: We have previously shown that 4 wk of exercise training early in life normalizes the otherwise greatly reduced pancreatic β-cell mass in adult male rats born small. The aim of the current study was to determine whether a similar normalization in adulthood of reduced skeletal muscle mitochondrial biogenesis markers and alterations in skeletal muscle lipids of growth-restricted male rats occurs following early exercise training. Bilateral uterine vessel ligation performed on day 18 of gestation resulted in Restricted offspring born small ( P 0.05) compared with both sham-operated Controls and a sham-operated Reduced litter group. Offspring remained sedentary or underwent treadmill running from 5–9 (early exercise) or 20–24 (later exercise) wk of age. At 24 wk of age, Restricted and Reduced litter offspring had lower ( P 0.05) skeletal muscle peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) protein expression compared with Control offspring. Early exercise training had the expected effect of increasing skeletal muscle markers of mitochondrial biogenesis, but, at this early age (9 wk), there was no deficit in Restricted and Reduced litter skeletal muscle mitochondrial biogenesis. Unlike our previous observations in pancreatic β-cell mass, there was no “reprogramming” effect of early exercise on adult skeletal muscle such that PGC-1α was lower in adult Restricted and Reduced litter offspring irrespective of exercise training. Later exercise training increased mitochondrial biogenesis in all groups. In conclusion, although the response to exercise training remains intact, early exercise training in rats born small does not have a reprogramming effect to prevent deficits in skeletal muscle markers of mitochondrial biogenesis in adulthood.
Publisher: Cambridge University Press (CUP)
Date: 10-11-2012
Publisher: American Physiological Society
Date: 11-2011
DOI: 10.1152/AJPENDO.00114.2011
Abstract: Fetal growth restriction is associated with reduced pancreatic β-cell mass, contributing to impaired glucose tolerance and diabetes. Exercise training increases β-cell mass in animals with diabetes and has long-lasting metabolic benefits in rodents and humans. We studied the effect of exercise training on islet and β-cell morphology and plasma insulin and glucose, following an intraperitoneal glucose tolerance test (IPGTT) in juvenile and adult male Wistar-Kyoto rats born small. Bilateral uterine vessel ligation performed on day 18 of pregnancy resulted in Restricted offspring born small compared with sham-operated Controls and also sham-operated Reduced litter offspring that had their litter size reduced to five pups at birth. Restricted, Control, and Reduced litter offspring remained sedentary or underwent treadmill running from 5 to 9 or 20 to 24 wk of age. Early life exercise increased relative islet surface area and β-cell mass across all groups at 9 wk, partially restoring the 60–68% deficit ( P 0.05) in Restricted offspring. Remarkably, despite no further exercise training after 9 wk, β-cell mass was restored in Restricted at 24 wk, while sedentary littermates retained a 45% deficit ( P = 0.05) in relative β-cell mass. Later exercise training also restored Restricted β-cell mass to Control levels. In conclusion, early life exercise training in rats born small restored β-cell mass in adulthood and may have beneficial consequences for later metabolic health and disease.
Publisher: Wiley
Date: 23-07-2013
Publisher: American Diabetes Association
Date: 13-01-2021
DOI: 10.2337/DC20-1893
Abstract: Evidence suggests that vitamin C supplementation could be a potential therapy in type 2 diabetes. However, its effectiveness and evidence quality require further evaluation. To investigate the efficacy of oral vitamin C supplementation in improving glycemic control, cardiovascular risk factors, and oxidative stress in people with type 2 diabetes. Databases (PubMed, Embase, Scopus, Cochrane Library) and clinical trial registries were searched for randomized controlled trials up to 8 September 2020. Trials in adults with type 2 diabetes were included. Trials were excluded if supplements were not exclusive to vitamin C and if & weeks in duration. Primary outcomes were HbA1c, glucose, cholesterol, triglycerides, and blood pressure (BP). Data were extracted for changes in outcomes between vitamin C and control groups. Evidence certainty was assessed using Grading of Recommendations, Assessment, Development, and Evaluation methods. Twenty-eight studies (N = 1,574 participants) were included in the review. Outcomes that changed to a statistically and clinically significant extent with vitamin C were systolic BP (mean difference −6.27 [95% CI −9.60, −2.96] mmHg P = 0.0002), with moderate evidence certainty, and HbA1c (−0.54% [−0.90, −0.17] P = 0.004) and diastolic BP (−3.77 [−6.13, −1.42] mmHg P = 0.002) with very low evidence certainty. Studies were predominantly short term (& months) with a small number of participants (n & 100). While evidence from short-term studies suggests that vitamin C supplementation may improve glycemic control and BP in people with type 2 diabetes, vitamin C supplementation cannot currently be recommended as a therapy until larger, long-term, and high-quality trials confirm these findings.
Publisher: American Physiological Society
Date: 04-2006
DOI: 10.1152/AJPENDO.00464.2005
Abstract: We compared in human skeletal muscle the effect of absolute vs. relative exercise intensity on AMP-activated protein kinase (AMPK) signaling and substrate metabolism under normoxic and hypoxic conditions. Eight untrained males cycled for 30 min under hypoxic conditions (11.5% O 2 , 111 ± 12 W, 72 ± 3% hypoxia V̇o 2 peak 72% Hypoxia) or under normoxic conditions (20.9% O 2 ) matched to the same absolute (111 ± 12 W, 51 ± 1% normoxia V̇o 2 peak 51% Normoxia) or relative (to V̇o 2 peak ) intensity (171 ± 18 W, 73 ± 1% normoxia V̇o 2 peak 73% Normoxia). Increases ( P 0.05) in AMPK activity, AMPKα Thr 172 phosphorylation, ACCβ Ser 221 phosphorylation, free AMP content, and glucose clearance were more influenced by the absolute than by the relative exercise intensity, being greatest in 73% Normoxia with no difference between 51% Normoxia and 72% Hypoxia. In contrast to this, increases in muscle glycogen use, muscle lactate content, and plasma catecholamine concentration were more influenced by the relative than by the absolute exercise intensity, being similar in 72% Hypoxia and 73% Normoxia, with both trials higher than in 51% Normoxia. In conclusion, increases in muscle AMPK signaling, free AMP content, and glucose disposal during exercise are largely determined by the absolute exercise intensity, whereas increases in plasma catecholamine levels, muscle glycogen use, and muscle lactate levels are more closely associated with the relative exercise intensity.
Publisher: American Physiological Society
Date: 04-2007
DOI: 10.1152/JAPPLPHYSIOL.00821.2006
Abstract: The purpose of the present study was to determine in human skeletal muscle whether a single exercise bout and 7 days of consecutive endurance (cycling) training 1) increased insulin-stimulated Akt pSer 473 and 2) altered the abundance of the protein tyrosine phosphatases (PTPases), PTP1B and SHP2. In healthy, untrained men ( n = 8 24 ± 1 yr), glucose infusion rate during a hyperinsulinemic euglycemic cl , when compared with untrained values, was not improved 24 h following a single 60-min bout of endurance cycling but was significantly increased (∼30% P 0.05) 24 h following completion of 7 days of exercise training. Insulin-stimulated Akt pSer 473 was ∼50% higher ( P 0.05) 24 h following the acute bout of exercise, with this effect remaining after 7 days of training ( P 0.05). Insulin-stimulated insulin receptor and insulin receptor substrate-1 tyrosine phosphorylation were not altered 24 h after acute exercise and short-term training. Insulin did not acutely regulate the localization of the PTPases, PTP1B or SHP2, although cytosolic protein abundance of SHP2 was increased ( P 0.05 main effect) 24 h following acute exercise and short-term training. In conclusion, insulin-sensitive Akt pSer 473 and cytosolic SHP2 protein abundance are higher after acute exercise and short-term training, and this effect appears largely due to the residual effects of the last bout of prior exercise. The significance of exercise-induced alterations in cytosolic SHP2 and insulin-stimulated Akt pSer 473 on the improvement in insulin sensitivity requires further elucidation.
Publisher: Wiley
Date: 08-2020
DOI: 10.14814/PHY2.14520
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2011
Publisher: American Diabetes Association
Date: 12-2007
DOI: 10.2337/DB07-0745
Abstract: OBJECTIVE—We have previously shown in humans that local infusion of a nitric oxide synthase (NOS) inhibitor into the femoral artery attenuates the increase in leg glucose uptake during exercise without influencing total leg blood flow. However, rodent studies examining the effect of NOS inhibition on contraction-stimulated skeletal muscle glucose uptake have yielded contradictory results. This study examined the effect of local infusion of an NOS inhibitor on skeletal muscle glucose uptake (2-deoxyglucose) and capillary blood flow (contrast-enhanced ultrasound) during in situ contractions in rats. RESEARCH DESIGN AND METHODS—Male hooded Wistar rats were anesthetized and one hindleg electrically stimulated to contract (2 Hz, 0.1 ms) for 30 min while the other leg rested. After 10 min, the NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME) (arterial concentration of 5 μmol/l) or saline was infused into the epigastric artery of the contracting leg. RESULTS—Local NOS inhibition had no effect on blood pressure, heart rate, or muscle contraction force. Contractions increased (P & 0.05) skeletal muscle NOS activity, and this was prevented by l-NAME infusion. NOS inhibition caused a modest significant (P & 0.05) attenuation of the increase in femoral blood flow during contractions, but importantly there was no effect on capillary recruitment. NOS inhibition attenuated (P & 0.05) the increase in contraction-stimulated skeletal muscle glucose uptake by ∼35%, without affecting AMP-activated protein kinase (AMPK) activation. CONCLUSIONS—NOS inhibition attenuated increases in skeletal muscle glucose uptake during contraction without influencing capillary recruitment, suggesting that NO is critical for part of the normal increase in skeletal muscle fiber glucose uptake during contraction.
Publisher: Wiley
Date: 12-2014
DOI: 10.14814/PHY2.12224
Publisher: American Physiological Society
Date: 11-2008
DOI: 10.1152/JAPPLPHYSIOL.01371.2007
Abstract: Short-term exercise training in humans attenuates AMP-activated protein kinase (AMPK) activation during subsequent exercise conducted at the same absolute workload. Short-term 5-aminoimidazole-4-carboxyamide- ribonucleoside (AICAR) administration in rats mimics exercise training on skeletal muscle in terms of increasing insulin sensitivity, mitochondrial enzymes, and GLUT4 content, but it is not known whether these adaptations are accompanied by reduced AMPK activation during subsequent exercise. We compared the effect of 10 days of treadmill training (60 min/day) with 10 days of AICAR administration (0.5 mg/g body weight ip) on subsequent AMPK activation during 45 min of treadmill exercise in male Sprague-Dawley rats. Compared with nonexercised control rats, acute exercise significantly ( P 0.05) increased AMPKα Thr 172 phosphorylation (p-AMPKα 1.6-fold) and ACCβ Ser 218 phosphorylation (p-ACCβ 4.9-fold) in the soleus and p-ACCβ 2.2-fold in the extensor digitorum longus. Ten days of exercise training abolished the increase in soleus p-AMPKα and attenuated the increase in p-ACCβ (nonsignificant 2-fold increase). Ten days of AICAR administration also attenuated the exercise-induced increases in AMPK signaling in the soleus although not as effectively as 10 days of exercise training (nonsignificant 1.3-fold increase in p-AMPKα significant 3-fold increase in p-ACCβ). The increase in skeletal muscle 2-deoxyglucose uptake during exercise was greater after either 10 days of exercise training or AICAR administration. In conclusion, 10 days of AICAR administration substantially mimics the effect of 10 days training on attenuating skeletal muscle AMPK activation in response to subsequent exercise.
Publisher: American Physiological Society
Date: 08-2019
DOI: 10.1152/JAPPLPHYSIOL.00904.2018
Abstract: Noncoding RNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) play roles in the development and homeostasis of nearly every tissue of the body, including the regulation of processes underlying heart growth. Cardiac hypertrophy can be classified as either physiological (beneficial heart growth) or pathological (detrimental heart growth), the latter of which results in impaired cardiac function and heart failure and is predictive of a higher incidence of death due to cardiovascular disease. Several miRNAs have a functional role in exercise-induced cardiac hypertrophy, while both miRNAs and lncRNAs are heavily involved in pathological heart growth and heart failure. The latter have the potential to act as an endogenous sponge RNA and interact with specific miRNAs to control cardiac hypertrophy, adding another level of complexity to our understanding of the regulation of cardiac muscle mass. In addition to tissue-specific effects, ncRNA-mediated tissue cross talk occurs via exosomes. In particular, miRNAs can be internalized in exosomes and secreted from various cardiac and vascular cell types to promote angiogenesis, as well as protection and repair of ischemic tissues. ncRNAs hold promising therapeutic potential to protect the heart against ischemic injury and aid in regeneration. Numerous preclinical studies have demonstrated the therapeutic potential of ncRNAs, specifically miRNAs, for the treatment of cardiovascular disease. Most of these studies employ antisense oligonucleotides to inhibit miRNAs of interest however, off-target effects often limit their potential to be translated to the clinic. In this context, approaches using viral and nonviral delivery tools are promising means to provide targeted delivery in vivo.
Publisher: Springer Science and Business Media LLC
Date: 23-04-2022
DOI: 10.1007/S00018-022-04265-7
Abstract: Major stores of glucose are found as glycogen in skeletal muscle and liver. Skeletal muscle is a heterogenous tissue, with cellular metabolic and contractile distinctions dependent on whether the cell (fibre) is slow-twitch (Type I) or fast-twitch (Type II). We hypothesised that proteins important for glycogen metabolism would be differentially abundant between these erse fibres. We further hypothesised that the cellular location of these proteins would be different in muscle s les between control (CON) and in iduals with type 2 diabetes (T2D). We dissected in idual muscle fibre segments from vastus lateralis skeletal muscle biopsy s les from CON and T2D and used cell-type-specific approaches to address muscle heterogeneity. We measured glycogen and glycogen-related proteins by immunoblotting techniques. A lower proportion of Type I fibres was found in muscle in T2D compared with CON. AMPK-β2, glycogen branching enzyme (GBE), glycogen debranching enzyme (GDE), and glycogen phosphorylase (GP) were differentially localized between fibre types and in fibres from CON and T2D in iduals. A key novel finding was that the majority of glycogen is loosely bound or cytosolic in location in human skeletal muscle. The proportion of this diffusible pool of glycogen was significantly lower in Type I fibres in T2D compared to CON. A hyperinsulinaemic, euglycaemic cl in people with type 2 diabetes had no effect on the proportion of diffusible glycogen. We identify cell-type as an important consideration when assessing glycogen metabolism in muscle. Our findings demonstrate varying glucose handling abilities in specific muscle fibre types in type 2 diabetes. A model is presented to provide an overview of the cell-specific differences in glycogen metabolism in type 2 diabetes.
Publisher: American Physiological Society
Date: 08-2012
DOI: 10.1152/AJPENDO.00667.2011
Abstract: Nitric oxide (NO) is an important vasodilator and regulator in the cardiovascular system, and this link was the subject of a Nobel prize in 1998. However, NO also plays many other regulatory roles, including thrombosis, immune function, neural activity, and gastrointestinal function. Low concentrations of NO are thought to have important signaling effects. In contrast, high concentrations of NO can interact with reactive oxygen species, causing damage to cells and cellular components. A less-recognized site of NO production is within skeletal muscle, where small increases are thought to have beneficial effects such as regulating glucose uptake and possibly blood flow, but higher levels of production are thought to lead to deleterious effects such as an association with insulin resistance. This review will discuss the role of NO in skeletal muscle during and following exercise, including in mitochondrial biogenesis, muscle efficiency, and blood flow with a particular focus on its potential role in regulating skeletal muscle glucose uptake during exercise.
Publisher: American Physiological Society
Date: 05-2014
DOI: 10.1152/AJPENDO.00456.2013
Abstract: In iduals born after intrauterine growth restriction (IUGR) are at an increased risk of developing diabetes in their adult life. IUGR impairs β-cell function and reduces β-cell mass, thereby diminishing insulin secretion. IUGR also induces insulin resistance, with impaired insulin signaling in muscle in adult humans who were small for gestational age (SGA) and in rodent models of IUGR. There is epidemiological evidence in humans that exercise in adults can reduce the risk of metabolic disease following IUGR. However, it is not clear whether adult IUGR in iduals benefit to the same extent from exercise as do normal-birth-weight in iduals, as our rat studies suggest less of a benefit in those born IUGR. Importantly, however, there is some evidence from studies in rats that exercise in early life might be able to reverse or reprogram the long-term metabolic effects of IUGR. Studies are needed to address gaps in current knowledge, including determining the mechanisms involved in the reprogramming effects of early exercise in rats, whether exercise early in life or in adulthood has similar beneficial metabolic effects in larger animal models in which insulin resistance develops after IUGR. Human studies are also needed to determine whether exercise training improves insulin secretion and insulin sensitivity to the same extent in IUGR adults as in control populations. Such investigations will have implications for customizing the recommended level and timing of exercise to improve metabolic health after IUGR.
Publisher: Cold Spring Harbor Laboratory
Date: 24-07-2023
DOI: 10.1101/2023.07.22.550175
Abstract: Cardiomyocyte calcium homeostasis is a tightly regulated process. The mitochondrial calcium uniporter (MCU) complex can buffer elevated cytosolic Ca 2+ levels and consists of pore-forming proteins including MCU, and various regulatory proteins such as mitochondrial calcium uptake proteins 1 and 2 (MICU1/2). The stoichiometry of these proteins influences the sensitivity to Ca 2+ and activity of the complex. However, the factors that regulate their gene expression remain incompletely understood. Long non-coding RNAs (lncRNAs) regulate gene expression through various mechanisms, and we recently found that the lncRNA Tug1 increased the expression of Mcu and associated genes. To further explore this, we performed antisense LNA knockdown of Tug1 ( Tug1 KD) in H9c2 rat cardiomyocytes. Tug1 KD increased MCU protein expression, yet pyruvate dehydrogenase dephosphorylation, which is indicative of mitochondrial Ca 2+ uptake was not enhanced. However, RNA-seq revealed that Tug1 KD increased Mcu along with differential expression of genes including many related to Ca 2+ regulation pathways in the heart. To understand the effect of this on Ca 2+ signalling, we measured phosphorylation of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) and its downstream target cAMP Response Element-Binding protein (CREB), a transcription factor known to drive Mcu gene expression. In response a Ca 2+ stimulus, the increase in CaMKII and CREB phosphorylation was attenuated by Tug1 KD. Inhibition of CaMKII, but not CREB, partially prevented the Tug1 KD- mediated increase in Mcu . Together, these data suggest that Tug1 modulates MCU expression via a mechanism involving CaMKII and regulates cardiomyocyte Ca 2+ signalling which could have important implications for cardiac function.
Publisher: Human Kinetics
Date: 2023
Abstract: This study compared the recommended dose of sodium citrate (SC, 500 mg/kg body mass) and sodium bicarbonate (SB, 300 mg/kg body mass) for blood alkalosis (blood [HCO 3 − ]) and gastrointestinal symptoms (GIS number and severity). Sixteen healthy in iduals ingested the supplements in a randomized, crossover design. Gelatin capsules were ingested over 15 min alongside a carbohydrate-rich meal, after which participants remained seated for forearm venous blood s le collection and completion of GIS questionnaires every 30 min for 300 min. Time-course and session value (i.e., peak and time to peak) comparisons of SC and SB supplementation were performed using linear mixed models. Peak blood [HCO 3 − ] was similar for SC (mean 34.2, 95% confidence intervals [33.4, 35.0] mmol/L) and SB (mean 33.6, 95% confidence intervals [32.8, 34.5] mmol/L, p = .308), as was delta blood [HCO 3 − ] (SC = 7.9 mmol/L SB = 7.3 mmol/L, p = .478). Blood [HCO 3 − ] was ≥6 mmol/L above baseline from 180 to 240 min postingestion for SC, significantly later than for SB (120–180 min p .001). GIS were mostly minor, and peaked 80–90 min postingestion for SC, and 35–50 min postingestion for SB. There were no significant differences for the number or severity of GIS reported ( p .05 for all parameters). In summary, the recommended doses of SC and SB induce similar blood alkalosis and GIS, but with a different time course.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.JSAMS.2017.06.002
Abstract: To explore the impact of uninterrupted sitting versus sitting with resistance-type activity breaks on adolescents' postprandial glucose responses while consuming a diet varying in energy. Cross-over randomised trial. Thirteen healthy participants (16.4±1.3years) completed a four-treatment cross-over trial: (1) uninterrupted sitting+high-energy diet (2) sitting with breaks+high-energy diet (3) uninterrupted sitting+standard-energy diet and (4) sitting with breaks+standard-energy diet. For all four conditions, two identical meals were consumed at 0h and 3h. A continuous glucose monitoring system (CGM) recorded interstitial glucose concentrations every five minutes. Linear mixed models examined differences in glucose positive incremental area under the curve (iAUC) and total AUC between the sitting and diet conditions for the first meal, second meal and entire trial period. Compared to the uninterrupted sitting conditions, the breaks condition elicited a 36.0mmol/L/h (95%CI 6.6-65.5) and 35.9mmol/L/h (95%CI 6.6-65.5) lower iAUC response after the first and second meal, respectively, but not for the entire trial period or for total AUC. Compared to the standard-energy diet, the high-energy diet elicited a 55.0mmol/L/h (95%CI 25.8-84.2) and 75.7mmol/L/h (95%CI 8.6-142.7) higher iAUC response after the first meal and entire trial, respectively. Similar response to the high-energy diet were observed for total AUC. According to iAUC, interrupting sitting had a significant effect on lowering postprandial glucose for both dietary conditions, however, it was not significant when examining total AUC. Larger studies are needed to confirm these findings. ACTRN12615001145594.
Publisher: American Physiological Society
Date: 2006
DOI: 10.1152/AJPENDO.00263.2005
Abstract: Nitric oxide synthase (NOS) inhibition has been shown in humans to attenuate exercise-induced increases in muscle glucose uptake. We examined the effect of infusing the NO precursor l-arginine (l-Arg) on glucose kinetics during exercise in humans. Nine endurance-trained males cycled for 120 min at 72 ± 1% V̇o 2 peak followed immediately by a 15-min “all-out” cycling performance bout. A [6,6- 2 H]glucose tracer was infused throughout exercise, and either saline alone (Control, CON) or saline containing l-Arg HCl (l-Arg, 30 g at 0.5 g/min) was coinfused in a double-blind, randomized order during the last 60 min of exercise. l-Arg augmented the increases in glucose rate of appearance, glucose rate of disappearance, and glucose clearance rate (l-Arg: 16.1 ± 1.8 ml·min −1 ·kg −1 CON: 11.9 ± 0.7 ml·min −1 ·kg −1 at 120 min, P 0.05) during exercise, with a net effect of reducing plasma glucose concentration during exercise. l-Arg infusion had no significant effect on plasma insulin concentration but attenuated the increase in nonesterified fatty acid and glycerol concentrations during exercise. l-Arg infusion had no effect on cycling exercise performance. In conclusion, l-Arg infusion during exercise significantly increases skeletal muscle glucose clearance in humans. Because plasma insulin concentration was unaffected by l-Arg infusion, greater NO production may have been responsible for this effect.
Publisher: Wiley
Date: 22-02-2013
DOI: 10.1111/APHA.12078
Publisher: Public Library of Science (PLoS)
Date: 28-12-2012
Publisher: Wiley
Date: 15-11-2020
DOI: 10.1113/JP280651
Abstract: Exercise, insulin‐infusion and low‐glucose mixed‐nutrient meal ingestion increases muscle microvascular blood flow which in part facilitates glucose delivery and disposal. In contrast, high‐glucose ingestion impairs muscle microvascular blood flow which may contribute to impaired postprandial metabolism. We investigated the effects of prior cycling exercise on postprandial muscle microvascular blood flow responses to a high‐glucose mixed‐nutrient meal ingested 3 and 24 h post‐exercise. Prior exercise enhanced muscle microvascular blood flow and mitigated microvascular impairments induced by a high‐glucose mixed meal ingested 3 h post‐exercise, and to a lesser extent 24 h post‐exercise. High‐glucose ingestion 3 h post‐exercise leads to greater postprandial blood glucose, non‐esterified fatty acids, and fat oxidation, and a delay in the insulin response to the meal compared to control. Effects of acute exercise on muscle microvascular blood flow persist well after the cessation of exercise which may be beneficial for conditions characterized by microvascular and glycaemic dysfunction. Exercise, insulin‐infusion and low‐glucose mixed‐nutrient meal ingestion lead to increased muscle microvascular blood flow (MBF), whereas high‐glucose ingestion impairs MBF. We investigated whether prior cycling exercise could enhance postprandial muscle MBF and prevent MBF impairments induced by high‐glucose mixed‐nutrient meal ingestion. In a randomized cross‐over design, eight healthy young men ingested a high‐glucose mixed‐nutrient meal (1.1 g glucose/kg body weight 45% carbohydrate, 20% protein and 35% fat) after an overnight fast (no‐exercise control) and 3 h and 24 h after moderate‐intensity cycling exercise (1 h at 70–75% ). Skeletal muscle MBF, measured directly by contrast‐enhanced ultrasound, was lower at 60 min and 120 min postprandially compared to baseline in all conditions ( P 0.05), with a greater decrease occurring from 60 min to 120 min in the control (no‐exercise) condition only ( P 0.001). Despite this meal‐induced decrease, MBF was still markedly higher compared to control in the 3 h post‐exercise condition at 0 min (pre‐meal 74%, P = 0.004), 60 min (112%, P = 0.002) and 120 min (223%, P 0.001), and in the 24 h post‐exercise condition at 120 min postprandially (132%, P 0.001). We also report that in the 3 h post‐exercise condition postprandial blood glucose, non‐esterified fatty acids (NEFAs), and fat oxidation were substantially elevated, and the insulin response to the meal delayed compared to control. This probably reflects a combination of increased post‐exercise exogenous glucose appearance, substrate competition, and NEFA‐induced insulin resistance. We conclude that prior cycling exercise elicits long‐lasting effects on muscle MBF and partially mitigates MBF impairments induced by high‐glucose mixed‐nutrient meal ingestion.
Publisher: American Physiological Society
Date: 09-2023
Abstract: This is the first time Australia-wide agreement has been reached on the core concepts of physiology with the Delphi method. Embedding of the core concepts will result in consistency in physiology curricula, improvements to teaching and learning, and benchmarking across Australian universities.
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.BBAGEN.2013.11.016
Abstract: Maintaining skeletal muscle mitochondrial content and function is important for sustained health throughout the lifespan. Exercise stimulates important key stress signals that control skeletal mitochondrial biogenesis and function. Perturbations in mitochondrial content and function can directly or indirectly impact skeletal muscle function and consequently whole-body health and wellbeing. This review will describe the exercise-stimulated stress signals and molecular mechanisms positively regulating mitochondrial biogenesis and function. It will then discuss the major myopathies, neuromuscular diseases and conditions such as diabetes and ageing that have dysregulated mitochondrial function. Finally, the impact of exercise and potential pharmacological approaches to improve mitochondrial function in diseased populations will be discussed. Exercise activates key stress signals that positively impact major transcriptional pathways that transcribe genes involved in skeletal muscle mitochondrial biogenesis, fusion and metabolism. The positive impact of exercise is not limited to younger healthy adults but also benefits skeletal muscle from diseased populations and the elderly. Impaired mitochondrial function can directly influence skeletal muscle atrophy and contribute to the risk or severity of disease conditions. Pharmacological manipulation of exercise-induced pathways that increase skeletal muscle mitochondrial biogenesis and function in critically ill patients, where exercise may not be possible, may assist in the treatment of chronic disease. This review highlights our understanding of how exercise positively impacts skeletal muscle mitochondrial biogenesis and function. Exercise not only improves skeletal muscle mitochondrial health but also enables us to identify molecular mechanisms that may be attractive targets for therapeutic manipulation. This article is part of a Special Issue entitled Frontiers of mitochondrial research.
Publisher: American Physiological Society
Date: 15-04-2013
DOI: 10.1152/AJPENDO.00568.2012
Abstract: The aim of this research was to examine the impact of the xanthine oxidase (XO) inhibitor allopurinol on the skeletal muscle activation of cell signaling kinases' and adaptations to mitochondrial proteins and antioxidant enzymes following acute endurance exercise and endurance training. Male Sprague-Dawley rats performed either acute exercise (60 min of treadmill running, 27 m/min, 5% incline) or 6 wk of endurance training (5 days/wk) while receiving allopurinol or vehicle. Allopurinol treatment reduced XO activity to 5% of the basal levels ( P 0.05), with skeletal muscle uric acid levels being almost undetectable. Following acute exercise, skeletal muscle oxidized glutathione (GSSG) significantly increased in allopurinol- and vehicle-treated groups despite XO activity and uric acid levels being unaltered by acute exercise ( P 0.05). This suggests that the source of ROS was not from XO. Surprisingly, muscle GSSG levels were significantly increased following allopurinol treatment. Following acute exercise, allopurinol treatment prevented the increase in p38 MAPK and ERK phosphorylation and attenuated the increase in mitochondrial transcription factor A (mtTFA) mRNA ( P 0.05) but had no effect on the increase in peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), nuclear respiratory factor-2, GLUT4, or superoxide dismutase mRNA. Allopurinol also had no impact on the endurance training-induced increases in PGC-1α, mtTFA, and mitochondrial proteins including cytochrome c, citrate synthase, and β-hydroxyacyl-CoA dehydrogenase. In conclusion, although allopurinol inhibits cell signaling pathways in response to acute exercise, the inhibitory effects of allopurinol appear unrelated to exercise-induced ROS production by XO. Allopurinol also has little effect on increases in mitochondrial proteins following endurance training.
Publisher: Springer Science and Business Media LLC
Date: 02-2002
Abstract: In healthy in iduals performing constant-load exercise at intensities above the lactate threshold a secondary rise in pulmonary oxygen uptake ([V]O(2)) occurs. [V]O(2) reaches a maximum and exhaustion rapidly prevails for a range of work rates lower than the maximal work rate achieved during a conventional rapid-incremental test. This phenomenon is called the slow component (SC) of [V]O(2) kinetics and represents an increase in [V]O(2) without an increase in work rate. Although still under debate, the magnitude of the SC is believed to be associated with the percentage of type II muscle fibres and their recruitment. In this study we investigated the relationship between the magnitude of the relative SC, citrate synthase activity, UCP2 and UCP3 mRNA levels and muscle fibre composition in both endurance-trained and recreationally active subjects. The magnitude of the relative SC was measured in 12 endurance-trained (Tr) and 15 recreationally active (RA) male subjects. The magnitude of the relative SC was determined as the difference between the end-exercise [V]O(2) and 3 min [V]O(2) ided by the difference between end-exercise [V]O(2) and baseline [V]O(2). UCP2 and UCP3 mRNA expression in the vastus lateralis was measured by RT-PCR with beta-actin mRNA used as an internal control. These values were also normalized against cytochrome-b mRNA to control for training induced changes in mitochondria when comparing the Tr and RA groups. Type I, IIa and IIx skeletal muscle fibre composition was determined using a routine myosin ATPase histochemical staining technique. Citrate synthase (CS) activity was measured using spectrophotometric detection. The magnitude of the relative SC of the Tr group had the highest correlation with citrate synthase activity (r=-0.90, P<0.001) and that of the RA group with [V]O(2) peak (r=-0.68, P<0.01). For the Tr group other correlations with the magnitude of the relative SC included UCP3 mRNA levels (r=0.69, P<0.05) and the percentage of type I fibres (r=-0.58, P<0.05), while for the RA group they included UCP3 mRNA (r=0.58, P<0.05) and the percentage of type IIa muscle fibres (r=0.59, P<0.05). The Tr subjects had a lower relative SC (P=0.04) and a lower expression of UCP2 (P=0.04), and UCP3 mRNA (P=0.01) than the RA subjects. When the groups were combined the magnitude of the relative SC correlated with UCP3 mRNA (r=0.70, P<0.01), percentage of type IIa muscle fibres (r=0.60, P<0.01) and [V]O(2) peak (r=-0.73, P<0.01). Additionally UCP3 mRNA correlated with the percentage of type IIa muscle fibres (r=0.63, P<0.001). Citrate synthase activity and [V]O(2) peak are indicators of aerobic fitness. The high negative correlations between the magnitude of the relative SC and citrate synthase activity and [V]O(2) peak, of the Tr and RA subjects, respectively, suggests that the magnitude of the relative SC is inversely correlated with aerobic fitness. Additionally the correlations between UCP3 mRNA and the magnitude of the relative SC for both groups in idually and combined suggest that the uncoupling activity of the UCP3 protein may also influence the magnitude of the relative SC.
Publisher: American Physiological Society
Date: 2007
DOI: 10.1152/JAPPLPHYSIOL.00549.2006
Abstract: The purpose of this study was to determine whether nitric oxide synthase (NOS) inhibition decreased basal and exercise-induced skeletal muscle mitochondrial biogenesis. Male Sprague-Dawley rats were assigned to one of four treatment groups: NOS inhibitor N G -nitro-l-arginine methyl ester (l-NAME, ingested for 2 days in drinking water, 1 mg/ml) followed by acute exercise, no l-NAME ingestion and acute exercise, rest plus l-NAME, and rest without l-NAME. The exercised rats ran on a treadmill for 53 ± 2 min and were then killed 4 h later. NOS inhibition significantly ( P 0.05 main effect) decreased basal peroxisome proliferator-activated receptor-γ coactivator 1β (PGC-1β) mRNA levels and tended ( P = 0.08) to decrease mtTFA mRNA levels in the soleus, but not the extensor digitorum longus (EDL) muscle. This coincided with significantly reduced basal levels of cytochrome c oxidase (COX) I and COX IV mRNA, COX IV protein and COX enzyme activity following NOS inhibition in the soleus, but not the EDL muscle. NOS inhibition had no effect on citrate synthase or β-hydroxyacyl CoA dehydrogenase activity, or cytochrome c protein abundance in the soleus or EDL. NOS inhibition did not reduce the exercise-induced increase in peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) mRNA in the soleus or EDL. In conclusion, inhibition of NOS appears to decrease some aspects of the mitochondrial respiratory chain in the soleus under basal conditions, but does not attenuate exercise-induced mitochondrial biogenesis in the soleus or in the EDL.
Publisher: American Physiological Society
Date: 08-2015
DOI: 10.1152/JAPPLPHYSIOL.01055.2014
Abstract: Hormesis encompasses the notion that low levels of stress stimulate or upregulate existing cellular and molecular pathways that improve the capacity of cells and organisms to withstand greater stress. This notion underlies much of what we know about how exercise conditions the body and induces long-term adaptations. During exercise, the body is exposed to various forms of stress, including thermal, metabolic, hypoxic, oxidative, and mechanical stress. These stressors activate biochemical messengers, which in turn activate various signaling pathways that regulate gene expression and adaptive responses. Historically, antioxidant supplements, nonsteroidal anti-inflammatory drugs, and cryotherapy have been favored to attenuate or counteract exercise-induced oxidative stress and inflammation. However, reactive oxygen species and inflammatory mediators are key signaling molecules in muscle, and such strategies may mitigate adaptations to exercise. Conversely, withholding dietary carbohydrate and restricting muscle blood flow during exercise may augment adaptations to exercise. In this review article, we combine, integrate, and apply knowledge about the fundamental mechanisms of exercise adaptation. We also critically evaluate the rationale for using interventions that target these mechanisms under the overarching concept of hormesis. There is currently insufficient evidence to establish whether these treatments exert dose-dependent effects on muscle adaptation. However, there appears to be some dissociation between the biochemical/molecular effects and functional erformance outcomes of some of these treatments. Although several of these treatments influence common kinases, transcription factors, and proteins, it remains to be determined if these interventions complement or negate each other, and whether such effects are strong enough to influence adaptations to exercise.
Publisher: Public Library of Science (PLoS)
Date: 13-09-2012
Publisher: American Physiological Society
Date: 06-2019
DOI: 10.1152/AJPENDO.00500.2018
Abstract: Currently, it is unclear whether short-term overfeeding in healthy people significantly affects postprandial glucose regulation, as most human overfeeding studies have utilized induced experimental conditions such as the euglycemic-hyperinsulinemic cl technique to assess glucoregulation. The aim of this study was to quantify glucose fluxes [rates of meal glucose appearance (R a ), disposal (R d ), and endogenous glucose production (EGP)] in response to 5 and 28 days of overfeeding (+45% energy) while maintaining habitual macronutrient composition (31.0 ± 1.9% fat, 48.6 ± 2.2% carbohydrate, 16.7 ± 1.4% protein) in healthy, lean young men. Meal tolerance testing was combined with the triple-stable isotope glucose tracer approach. Visceral adipose volume increased by ~15% with 5 days of overfeeding, while there was no further change at 28 days. In contrast, body mass (+1.6 kg) and fat mass (+1.3 kg) were significantly increased only after 28 days of overfeeding. Fasting EGP, R d , and insulin were increased at 5 but unchanged after 28 days. Postprandial glucose and insulin responses were unaltered by 5 days of overfeeding but were modestly increased after 28 days ( P 0.05). However, meal R a and glucose R d were significantly increased after both 5 and 28 days of overfeeding ( P 0.05). Despite this, overfeeding did not lead to alterations to postprandial EGP suppression. Thus, in contrast to findings from euglycemic-hyperinsulinemic cl studies, chronic overfeeding did not affect the ability to suppress EGP or stimulate R d under postprandial conditions. Rather, glucose flux was appropriately maintained following 28 days of overfeeding through modest increases in postprandial glycemia and insulinemia.
Publisher: Wiley
Date: 02-2008
Publisher: Elsevier BV
Date: 08-2020
Publisher: Wiley
Date: 28-02-2023
Abstract: Obesity is a major public health crisis, with 1.6 billion adults worldwide being classified as overweight or obese in 2014. Therefore, it is not surprising that the number of women who are overweight or obese at the time of conception is increasing. Obesity during pregnancy is associated with the development of gestational diabetes and preecl sia. The developmental origins of health and disease hypothesis proposes that perturbations during critical stages of development can result in adverse fetal changes that leads to an increased risk of developing diseases in adulthood. Of particular concern, children born to obese mothers are at a greater risk of developing cardiometabolic disease. One subset of the population who are predisposed to developing obesity are children born small for gestational age, which occurs in 10% of pregnancies worldwide. Epidemiological studies report that these growth-restricted children have an increased susceptibility to type 2 diabetes, obesity, and hypertension. Importantly during pregnancy, growth-restricted females have a higher risk of developing cardiometabolic disease, indicating that they may have an exacerbated phenotype if they are also overweight or obese. Thus, the development of early pregnancy interventions targeted to obese mothers may prevent their children from developing cardiometabolic disease in adulthood.
Publisher: Elsevier BV
Date: 06-1998
DOI: 10.1016/S1440-2440(98)80018-2
Abstract: A large number of team games require participants to repeatedly produce maximal or near maximal sprints of short duration with brief recovery periods. The purpose of the present study was to determine the relationship between a repeated sprint ability (RSA) test that is specific to the energy demands of Australian Rules football (ARF), and the aerobic and anaerobic energy systems. Seventeen ARF players participated in the study. Each participant was assessed for VO2 max, accumulated oxygen deficit (AOD), best 20 m sprint time and RSA. The RSA test involved 12x20 m sprints departing every 20 s. When including the work performed during the time taken to decelerate, the test involved a work to rest ratio of approximately 1:3. Total sprinting time and the percentage decrement of repeated sprinting times were the two derived measures of RSA. The results indicate that the best 20 m sprint time was the only factor to correlate significantly with total sprinting time (r = 0.829, P < 0.001) and percentage decrement (r = -0.722, P < 0.01). VO2 max and AOD were not related to the total sprinting time or the percentage decrement that was produced by the RSA test. This was interpreted to signify that the phosphagen system was the major energy contributor for this test.
Publisher: American Physiological Society
Date: 03-2010
DOI: 10.1152/JAPPLPHYSIOL.00377.2009
Abstract: 5-Aminoimidazole-4-carboxamide-ribonucleoside (AICAR) and caffeine, which activate AMP-activated protein kinase (AMPK) and cause sarcoplasmic reticulum calcium release, respectively, have been shown to increase mitochondrial biogenesis in L6 myotubes. Nitric oxide (NO) donors also increase mitochondrial biogenesis. Since neuronal and endothelial NO synthase (NOS) are calcium dependent and are also phosphorylated by AMPK, we hypothesized that NOS inhibition would attenuate the activation of mitochondrial biogenesis in response to AICAR and caffeine. L6 myotubes either were not treated (control) or were exposed acutely or for 5 h/day over 5 days to 100 μM of N G -nitro-l-arginine methyl ester (l-NAME, NOS inhibitor), 100 μM S-nitroso- N-acetyl-penicillamine (SNAP) (NO donor) ± 100 μM l-NAME, 2 mM AICAR ± 100 μM l-NAME, or 5 mM caffeine ± 100 μM l-NAME ( n = 12/treatment). Acute AICAR administration increased ( P 0.05) phospho- (P-)AMPK, but also increased P-CaMK, with resultant chronic increases in peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), cytochrome- c oxidase (COX)-1, and COX-4 protein expression compared with control cells. NOS inhibition, which had no effect on AICAR-stimulated P-AMPK, surprisingly increased P-CaMK and attenuated the AICAR-induced increases in COX-1 and COX-4 protein. Caffeine administration, which increased P-CaMK without affecting P-AMPK, increased COX-1, COX-4, PGC-1α, and citrate synthase activity. NOS inhibition, surprisingly, greatly attenuated the effect of caffeine on P-CaMK and attenuated the increases in COX-1 and COX-4 protein. SNAP increased all markers of mitochondrial biogenesis, and it also increased P-AMPK and P-CaMK. In conclusion, AICAR and caffeine increase mitochondrial biogenesis in L6 myotubes, at least in part, via interactions with NOS.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.FREERADBIOMED.2016.02.022
Abstract: Recent research highlights the importance of redox signalling pathway activation by contraction-induced reactive oxygen species (ROS) and nitric oxide (NO) in normal exercise-related cellular and molecular adaptations in skeletal muscle. In this review, we discuss some potentially important redox signalling pathways in skeletal muscle that are involved in acute and chronic responses to contraction and exercise. Specifically, we discuss redox signalling implicated in skeletal muscle contraction force, mitochondrial biogenesis and antioxidant enzyme induction, glucose uptake and muscle hypertrophy. Furthermore, we review evidence investigating the impact of major exogenous antioxidants on these acute and chronic responses to exercise. Redox signalling pathways involved in adaptive responses in skeletal muscle to exercise are not clearly elucidated at present, and further research is required to better define important signalling pathways involved. Evidence of beneficial or detrimental effects of specific antioxidant compounds on exercise adaptations in muscle is similarly limited, particularly in human subjects. Future research is required to not only investigate effects of specific antioxidant compounds on skeletal muscle exercise adaptations, but also to better establish mechanisms of action of specific antioxidants in vivo. Although we feel it remains somewhat premature to make clear recommendations in relation to application of specific antioxidant compounds in different exercise settings, a bulk of evidence suggests that N-acetylcysteine (NAC) is ergogenic through its effects on maintenance of muscle force production during sustained fatiguing events. Nevertheless, a current lack of evidence from studies using performance tests representative of athletic competition and a potential for adverse effects with high doses (>70mg/kg body mass) warrants caution in its use for performance enhancement. In addition, evidence implicates high dose vitamin C (1g/day) and E (≥260 IU/day) supplementation in impairments to some skeletal muscle cellular adaptations to chronic exercise training. Thus, determining the utility of antioxidant supplementation in athletes likely requires a consideration of training and competition periodization cycles of athletes in addition to type, dose and duration of antioxidant supplementation.
Publisher: American Physiological Society
Date: 11-2022
DOI: 10.1152/AJPENDO.00109.2022
Abstract: Adipose tissue blood flow plays a key role in postprandial nutrient storage. People at-risk of type 2 diabetes have impaired postmeal adipose tissue blood flow. Impaired adipose tissue blood flow is associated with altered fat oxidation. Risk of type 2 diabetes may be elevated by poor adipose tissue blood flow.
Publisher: Wiley
Date: 05-12-2019
Publisher: Elsevier BV
Date: 2013
DOI: 10.1016/J.NBD.2012.08.015
Abstract: Skeletal muscle mitochondrial dysfunction is believed to play a role in the progression and severity of amyotrophic lateral sclerosis (ALS). The regulation of transcriptional co-activators involved in mitochondrial biogenesis and function in ALS is not well known. When compared with healthy control subjects, patients with ALS, but not neurogenic disease (ND), had lower levels of skeletal muscle peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) mRNA and protein and estrogen-related receptor-α (ERRα) and mitofusin-2 (Mfn2) mRNA. PGC-1β, nuclear respiratory factor-1 (NRF-1) and Mfn1 mRNA as well as cytochrome C oxidase subunit IV (COXIV) mRNA and protein were lower in patients with ALS and ND. Both patient groups had reductions in citrate synthase and cytochrome c oxidase activity. Similar observations were made in skeletal muscle from transgenic ALS G93A transgenic mice. In vitro, PGC-1α and PGC-1β regulated Mfn1 and Mfn2 in an ERRα-dependent manner. Compared to healthy controls, miRNA 23a, 29b, 206 and 455 were increased in skeletal muscle of ALS patients. miR-23a repressed PGC-1α translation in a 3' UTR dependent manner. Transgenic mice over expressing miR-23a had a reduction in PGC-1α, cytochome-b and COXIV protein levels. These results show that skeletal muscle mitochondrial dysfunction in ALS patients is associated with a reduction in PGC-1α signalling networks involved in mitochondrial biogenesis and function, as well as increases in several miRNAs potentially implicated in skeletal muscle and neuromuscular junction regeneration. As miR-23a negatively regulates PGC-1α signalling, therapeutic inhibition of miR-23a may be a strategy to rescue PGC-1α activity and ameliorate skeletal muscle mitochondrial function in ALS.
Publisher: Springer Science and Business Media LLC
Date: 29-09-2022
DOI: 10.1007/S00125-021-05572-7
Abstract: Microvascular blood flow (MBF) increases in skeletal muscle postprandially to aid in glucose delivery and uptake in muscle. This vascular action is impaired in in iduals who are obese or have type 2 diabetes. Whether MBF is impaired in normoglycaemic people at risk of type 2 diabetes is unknown. We aimed to determine whether apparently healthy people at risk of type 2 diabetes display impaired skeletal muscle microvascular responses to a mixed-nutrient meal. In this cross-sectional study, participants with no family history of type 2 diabetes (FH-) for two generations (n = 18), participants with a positive family history of type 2 diabetes (FH+ i.e. a parent with type 2 diabetes n = 16) and those with type 2 diabetes (n = 12) underwent a mixed meal challenge (MMC). Metabolic responses (blood glucose, plasma insulin and indirect calorimetry) were measured before and during the MMC. Skeletal muscle large artery haemodynamics (2D and Doppler ultrasound, and Mobil-O-graph) and microvascular responses (contrast-enhanced ultrasound) were measured at baseline and 1 h post MMC. Despite normal blood glucose concentrations, FH+ in iduals displayed impaired metabolic flexibility (reduced ability to switch from fat to carbohydrate oxidation vs FH- p < 0.05) during the MMC. The MMC increased forearm muscle microvascular blood volume in both the FH- (1.3-fold, p < 0.01) and FH+ (1.3-fold, p < 0.05) groups but not in participants with type 2 diabetes. However, the MMC increased MBF (1.9-fold, p < 0.01), brachial artery diameter (1.1-fold, p < 0.01) and brachial artery blood flow (1.7-fold, p < 0.001) and reduced vascular resistance (0.7-fold, p < 0.001) only in FH- participants, with these changes being absent in FH+ and type 2 diabetes. Participants with type 2 diabetes displayed significantly higher vascular stiffness (p < 0.001) compared with those in the FH- and FH+ groups however, vascular stiffness did not change during the MMC in any participant group. Normoglycaemic FH+ participants display impaired postprandial skeletal muscle macro- and microvascular responses, suggesting that poor vascular responses to a meal may contribute to their increased risk of type 2 diabetes. We conclude that vascular insulin resistance may be an early precursor to type 2 diabetes in humans, which can be revealed using an MMC.
Publisher: Wiley
Date: 29-10-2008
DOI: 10.1111/J.1440-1681.2008.05038.X
Abstract: 1. The present review discusses the potential role of nitric oxide (NO) in the: (i) regulation of skeletal muscle glucose uptake during exercise and (ii) activation of mitochondrial biogenesis after exercise. 2. We have shown in humans that local infusion of an NO synthase inhibitor during exercise attenuates increases in skeletal muscle glucose uptake without affecting blood flow. Recent studies from our laboratory in rodents support these findings in humans, although rodent studies from other laboratories have yielded conflicting results. 3. There is clear evidence that NO increases mitochondrial biogenesis in non-contracting cells and that NO influences basal skeletal muscle mitochondrial biogenesis. However, there have been few studies examining the potential role of NO in the activation of mitochondrial biogenesis following an acute bout of exercise or in response to exercise training. Early indications are that NO is not involved in regulating the increase in mitochondrial biogenesis that occurs in response to exercise. 4. Exercise is considered the best prevention and treatment option for diabetes, but unfortunately many people with diabetes do not or cannot exercise regularly. Alternative therapies are therefore critical to effectively manage diabetes. If skeletal muscle NO is found to play an important role in regulating glucose uptake and/or mitochondrial biogenesis, pharmaceutical agents designed to mimic these effects of exercise may improve glycaemic control.
Publisher: Wiley
Date: 02-2022
DOI: 10.1113/JP282428
Abstract: Insulin infusion increases skeletal muscle microvascular blood flow (MBF) in healthy people but is impaired during insulin resistance. However, we have shown that eliciting insulin secretion via oral glucose loading in healthy people impairs muscle MBF, whilst others have demonstrated intravenous glucose infusion stimulates MBF. We aimed to show that the route of glucose administration (oral versus intravenous) influences muscle MBF, and explore potential gut‐derived hormones that may explain these ergent responses. Ten healthy in iduals underwent a 120 min oral glucose tolerance test (OGTT 75 g glucose) and on a subsequent occasion an intravenous glucose tolerance test (IVGTT, bypassing the gut) matched for similar blood glucose excursions. Femoral artery and thigh muscle microvascular (contrast‐enhanced ultrasound) haemodynamics were measured at baseline and during the OGTT/IVGTT. Plasma insulin, C‐peptide, glucagon, non‐esterified fatty acids and a range of gut‐derived hormones and incretins (gastric inhibitory polypeptide (GIP) and glucagon‐like peptide‐1(GLP‐1)) were measured at baseline and throughout the OGTT/IVGTT. The IVGTT increased whereas the OGTT impaired MBF (1.3‐fold versus 0.5‐fold from baseline, respectively, P = 0.0006). The impairment in MBF during the OGTT occurred despite producing 2.8‐fold higher plasma insulin concentrations ( P = 0.0001). The change in MBF from baseline (ΔMBF) negatively correlated with ΔGIP concentrations ( r = −0.665, P 0.0001). The natural log ratio of incretins GLP‐1:GIP was positively associated with ΔMBF ( r = 0.658, P 0.0001), suggesting they have opposing actions on the microvasculature. Postprandial hyperglycaemia per se does not acutely determine opposing microvascular responses between OGTT and IVGTT. Incretins may play a role in modulating skeletal muscle MBF in humans. Insulin or mixed nutrient meals stimulate skeletal muscle microvascular blood flow (MBF) to aid in the delivery of nutrients however, this vascular effect is lost during insulin resistance. Food/drinks containing large glucose loads impair MBF in healthy people however, this impairment is not observed when glucose is infused intravenously (bypassing the gut). We investigated skeletal muscle MBF responses to a 75 g oral glucose tolerance test and intravenous glucose infusion and aimed to identify potential gut hormones responsible for glucose‐mediated changes in MBF. Despite similar blood glucose concentrations, orally ingested glucose impaired, whereas intravenously infused glucose augmented, skeletal muscle MBF. The incretin gastric inhibitory polypeptide was negatively associated with MBF, suggestive of an incretin‐mediated MBF response to oral glucose ingestion. This work provides new insight into why diets high in glucose may be detrimental to vascular health and provides new avenues for novel treatment strategies targeting microvascular dysfunction.
Publisher: Springer Science and Business Media LLC
Date: 03-2004
DOI: 10.1007/S00125-003-1322-2
Abstract: Recruitment of the protein c-Cbl to the insulin receptor (IR) and its tyrosine phosphorylation via a pathway that is independent from phosphatidylinositol 3'-kinase is necessary for insulin-stimulated GLUT4 translocation in 3T3-L1 adipocytes. The activation of this pathway by insulin or exercise has yet to be reported in skeletal muscle. Lean and obese Zucker rats were randomly assigned to one of three treatment groups: (i). control, (ii). insulin-stimulated or (iii). acute, exhaustive exercise. Hind limb skeletal muscle was removed and the phosphorylation state of IR, Akt and c-Cbl measured. Insulin receptor phosphorylation was increased 12-fold after insulin stimulation ( p<0.0001) in lean rats and threefold in obese rats. Acute exercise had no effect on IR tyrosine phosphorylation. Similar results were found for serine phosphorylation of Akt. Exercise did not alter c-Cbl tyrosine phosphorylation in skeletal muscle of lean or obese rats. However, in contrast to previous studies in adipocytes, c-Cbl tyrosine phosphorylation was reduced after insulin treatment ( p<0.001). We also found that c-Cbl associating protein expression is relatively low in skeletal muscle of Zucker rats compared to 3T3-L1 adipocytes and this could account for the reduced c-Cbl tyrosine phosphorylation after insulin treatment. Interestingly, basal levels of c-Cbl tyrosine phosphorylation were higher in skeletal muscle from insulin-resistant Zucker rats ( p<0.05), but the physiological relevance is not clear. We conclude that the regulation of c-Cbl phosphorylation in skeletal muscle differs from that previously reported in adipocytes.
Publisher: Springer Science and Business Media LLC
Date: 08-06-2022
DOI: 10.1038/S41387-022-00209-Z
Abstract: There is increasing evidence that skeletal muscle microvascular (capillary) blood flow plays an important role in glucose metabolism by increasing the delivery of glucose and insulin to the myocytes. This process is impaired in insulin-resistant in iduals. Studies suggest that in diet-induced insulin-resistant rodents, insulin-mediated skeletal muscle microvascular blood flow is impaired post-short-term high fat feeding, and this occurs before the development of myocyte or whole-body insulin resistance. These data suggest that impaired skeletal muscle microvascular blood flow is an early vascular step before the onset of insulin resistance. However, evidence of this is still lacking in humans. In this review, we summarise what is known about short-term high-calorie and/or high-fat feeding in humans. We also explore selected animal studies to identify potential mechanisms. We discuss future directions aimed at better understanding the ‘early’ vascular mechanisms that lead to insulin resistance as this will provide the opportunity for much earlier screening and timing of intervention to assist in preventing type 2 diabetes.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.FREERADBIOMED.2015.10.412
Abstract: It is clear that reactive oxygen species (ROS) produced during skeletal muscle contraction have a regulatory role in skeletal muscle adaptation to endurance exercise. However, there is much controversy in the literature regarding whether attenuation of ROS by antioxidant supplementation can prevent these cellular adaptations. Therefore, the aim of this study was to determine whether vitamin C and E supplementation attenuates performance and cellular adaptations following acute endurance exercise and endurance training. A double-blinded, placebo-controlled randomized control trial was conducted in eleven healthy young males. Participants were matched for peak oxygen consumption (VO 2peak) and randomly allocated to placebo or antioxidant (vitamin C (2 × 500 mg/day) and E (400 IU/day)) groups. Following a four-week supplement loading period, participants completed acute exercise (10 × 4 min cycling at 90% VO 2peak, 2 min active recovery). Vastus lateralis muscle s les were collected pre-, immediately-post- and 3h-post-exercise. Participants then completed four weeks of training (3 days/week) using the aforementioned exercise protocol while continuing supplementation. Following exercise training, participants again completed an acute exercise bout with muscle biopsies. Acute exercise tended to increase skeletal muscle oxidative stress as measured by oxidized glutathione (GSSG) (P=0.058) and F2-isoprostanes (P=0.056), with no significant effect of supplementation. Acute exercise significantly increased mRNA levels of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), mitochondrial transcription factor A (TFAM) and PGC related coactivator (PRC), with no effect of supplementation. Following endurance training, supplementation did not prevent significantly increased VO 2peak, skeletal muscle levels of citrate synthase activity or mRNA or protein abundance of cytochrome oxidase subunit 4 (COX IV) (P<0.05). However, following training, vitamin C and E supplementation significantly attenuated increased skeletal muscle superoxide dismutase (SOD) activity and protein abundance of SOD2 and TFAM. Following acute exercise, supplementation with vitamin C and E did not attenuate skeletal muscle oxidative stress or increased gene expression of mitochondrial biogenesis markers. However, supplementation attenuated some (SOD, TFAM) of the increased skeletal muscle adaptations following training in healthy young men.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2011
Publisher: Wiley
Date: 30-04-2010
Publisher: American Physiological Society
Date: 09-2006
DOI: 10.1152/AJPENDO.00023.2006
Abstract: There is evidence that increasing carbohydrate (CHO) availability during exercise by raising preexercise muscle glycogen levels attenuates the activation of AMPKα2 during exercise in humans. Similarly, increasing glucose levels decreases AMPKα2 activity in rat skeletal muscle in vitro. We examined the effect of CHO ingestion on skeletal muscle AMPK signaling during exercise in nine active male subjects who completed two 120-min bouts of cycling exercise at 65 ± 1% V̇o 2 peak . In a randomized, counterbalanced order, subjects ingested either an 8% CHO solution or a placebo solution during exercise. Compared with the placebo trial, CHO ingestion significantly ( P 0.05) increased plasma glucose levels and tracer-determined glucose disappearance. Exercise-induced increases in muscle-calculated free AMP (17.7- vs. 11.8-fold), muscle lactate (3.3- vs. 1.8-fold), and plasma epinephrine were reduced by CHO ingestion. However, the exercise-induced increases in skeletal muscle AMPKα2 activity, AMPKα2 Thr 172 phosphorylation and acetyl-CoA Ser 222 phosphorylation, were essentially identical in the two trials. These findings indicate that AMPK activation in skeletal muscle during exercise in humans is not sensitive to changes in plasma glucose levels in the normal range. Furthermore, the rise in plasma epinephrine levels in response to exercise was greatly suppressed by CHO ingestion without altering AMPK signaling, raising the possibility that epinephrine does not directly control AMPK activity during muscle contraction under these conditions in vivo.
Publisher: American Physiological Society
Date: 05-2018
DOI: 10.1152/AJPENDO.00316.2017
Abstract: The effect of endurance exercise on enhancing insulin sensitivity and glucose flux has been well established with techniques such as the hyperinsulinemic cl . Although informative, such techniques do not emulate the physiological postprandial state, and it remains unclear how exercise improves postprandial glycaemia. Accordingly, combining mixed-meal tolerance testing and the triple-stable isotope glucose tracer approach, glucose fluxes [rates of meal glucose appearance (Ra), disposal (Rd), and endogenous glucose production (EGP)] were determined following acute endurance exercise (1 h cycling ~70% V̇o 2max ) and 4 wk of endurance training (cycling 5 days/wk). Training was associated with a modest increase in V̇o 2max (~7%, P 0.001). Postprandial glucose and insulin responses were reduced to the same extent following acute and chronic training. Interestingly, this was not accompanied by changes to rates of meal Ra, Rd, or degree of EGP suppression. Glucose clearance (Rd relative to prevailing glucose) was, however, enhanced with acute and chronic exercise. Furthermore, the duration of EGP suppression was shorter with acute and chronic exercise, with EGP returning toward fasting levels more rapidly than pretraining conditions. These findings suggest that endurance exercise influences the efficiency of the glucoregulatory system, where pretraining rates of glucose disposal and production were achieved at lower glucose and insulin levels. Notably, there was no influence of chronic training over and above that of a single exercise bout, providing further evidence that glucoregulatory benefits of endurance exercise are largely attributed to the residual effects of the last exercise bout.
Publisher: American Physiological Society
Date: 06-2020
DOI: 10.1152/AJPENDO.00540.2019
Abstract: Oral glucose ingestion leads to impaired muscle microvascular blood flow (MBF), which may contribute to acute hyperglycemia-induced insulin resistance. We investigated whether incorporating lipids and protein into a high-glucose load would prevent postprandial MBF dysfunction. Ten healthy young men (age, 27 yr [24, 30], mean with lower and upper bounds of the 95% confidence interval height, 180 cm [174, 185] weight, 77 kg [70, 84]) ingested a high-glucose (1.1 g/kg glucose) mixed-nutrient meal (10 kcal/kg 45% carbohydrate, 20% protein, and 35% fat) in the morning after an overnight fast. Femoral arterial blood flow was measured via Doppler ultrasound, and thigh MBF was measured via contrast-enhanced ultrasound, before meal ingestion and 1 h and 2 h postprandially. Blood glucose and plasma insulin were measured at baseline and every 15 min throughout the 2-h postprandial period. Compared with baseline, thigh muscle microvascular blood volume, velocity, and flow were significantly impaired at 60 min postprandial (−25%, −27%, and −46%, respectively all P 0.05) and to a greater extent at 120 min postprandial (−37%, −46%, and −64% all P 0.01). Heart rate and femoral arterial diameter, blood velocity, and blood flow were significantly increased at 60 min and 120 min postprandial (all P 0.05). Higher blood glucose area under the curve was correlated with greater MBF dysfunction ( R 2 = 0.742 P 0.001). Ingestion of a high-glucose mixed-nutrient meal impairs MBF in healthy in iduals for up to 2 h postprandial.
Publisher: Wiley
Date: 02-2016
DOI: 10.14814/PHY2.12720
Publisher: American Physiological Society
Date: 05-2008
DOI: 10.1152/AJPENDO.00037.2008
Abstract: Uteroplacental insufficiency has been shown to impair insulin action and glucose homeostasis in adult offspring and may act in part via altered mitochondrial biogenesis and lipid balance in skeletal muscle. Bilateral uterine vessel ligation to induce uteroplacental insufficiency in offspring (Restricted) or sham surgery was performed on day 18 of gestation in rats. To match the litter size of Restricted offspring, a separate cohort of sham litters had litter size reduced to five at birth (Reduced Litter), which also restricted postnatal growth. Remaining litters from sham mothers were unaltered (Control). Offspring were studied at 6 mo of age. In males, both Restricted and Reduced Litter offspring had reduced gastrocnemius PPARγ coactivator-1α (PGC-1α) mRNA and protein, and mitochondrial transcription factor A (mtTFA) and cytochrome oxidase (COX) III mRNA ( P 0.05), whereas only Restricted had reduced skeletal muscle COX IV mRNA and protein and glycogen ( P 0.05), despite unaltered glucose tolerance, homeostasis model assessment (HOMA) and intramuscular triglycerides. In females, only gastrocnemius mtTFA mRNA was lower in Reduced Litter offspring ( P 0.05). Furthermore, glucose tolerance was not altered in any female offspring, although HOMA and intramuscular triglycerides increased in Restricted offspring ( P 0.05). It is concluded that restriction of growth due to uteroplacental insufficiency alters skeletal muscle mitochondrial biogenesis and metabolic characteristics, such as glycogen and lipid levels, in a sex-specific manner in the adult rat in the absence of impaired glucose tolerance. Furthermore, an adverse postnatal environment induced by reducing litter size also restricts growth and alters skeletal muscle mitochondrial biogenesis and metabolic characteristics in the adult rat.
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.FREERADBIOMED.2014.09.013
Abstract: Antioxidant vitamin C (VC) supplementation is of potential clinical benefit to in iduals with skeletal muscle oxidative stress. However, there is a paucity of data reporting on the bioavailability of high-dose oral VC in human skeletal muscle. We aimed to establish the time course of accumulation of VC in skeletal muscle and plasma during high-dose VC supplementation in healthy in iduals. Concurrently we investigated the effects of VC supplementation on expression levels of the key skeletal muscle VC transporter sodium-dependent vitamin C transporter 2 (SVCT2) and intramuscular redox and mitochondrial measures. Eight healthy males completed a randomized placebo-controlled, crossover trial involving supplementation with ascorbic acid (2×500 mg/day) over 42 days. Participants underwent muscle and blood s ling on days 0, 1, 7, and 42 during each treatment. VC supplementation significantly increased skeletal muscle VC concentration after 7 days, which was maintained at 42 days (VC 3.0±0.2 (mean±SEM) to 3.9±0.4 mg/100 g wet weight (ww) versus placebo 3.1±0.3 to 2.9±0.2 mg/100 g ww, p=0.001). Plasma VC increased after 1 day, which was maintained at 42 days (VC 61.0±6.1 to 111.5±10.4 µmol/L versus placebo 60.7±5.3 to 59.2±4.8 µmol/L, p<0.001). VC supplementation significantly increased skeletal muscle SVCT2 protein expression (main treatment effect p=0.006) but did not alter skeletal muscle redox measures or citrate synthase activity. A main finding of our study was that 7 days of high-dose VC supplementation was required to significantly increase skeletal muscle vitamin C concentration in healthy males. Our findings implicate regular high-dose vitamin C supplementation as a means to safely increase skeletal muscle vitamin C concentration without impairing intramuscular ascorbic acid transport, antioxidant concentrations, or citrate synthase activity.
Publisher: Wiley
Date: 18-12-2018
DOI: 10.1113/JP275339
Publisher: American Physiological Society
Date: 11-2018
DOI: 10.1152/PHYSIOLGENOMICS.00042.2018
Abstract: Background and aims: Fetal and postnatal growth restriction cause a predisposition to cardiovascular disease (CVD) in adulthood. Telomeres are repetitive DNA-protein structures that protect chromosome ends, and the loss of these repeats (a reduction in telomere length) is associated with CVD. As exercise preserves telomere length and cardiovascular health, the aim of this study was to determine the effects of growth restriction and exercise training on cardiac telomere length and telomeric genes. Methods and results: Pregnant Wistar Kyoto rats underwent bilateral uterine vessel ligation to induce uteroplacental insufficiency and fetal growth restriction (“Restricted”). Sham-operated rats had either intact litters (“Control”) or their litters reduced to five pups with slowed postnatal growth (“Reduced”). Control, Restricted, and Reduced male rats were assigned to Sedentary, Early exercise (5–9 wk of age), or Late exercise (20–24 wk of age) groups. Hearts were excised at 24 wk of age for telomere length and gene expression measurements by quantitative PCR. Growth restriction shortened cardiac telomere length ( P 0.001), but this was rescued by early exercise ( P 0.001). Early and Late exercise increased cardiac weight index ( P 0.001), but neither this nor telomere length was associated with expression of the telomeric genes Tert, Terc, Trf2, Pnuts, or Sirt1. Discussion and conclusions: Growth restriction shortens cardiac telomere length, reflecting the cardiac pathologies associated with low birth weight. Exercise in early life may offer long-term protective effects on cardiac telomere length, which could help prevent CVD in later life.
Publisher: Cambridge University Press (CUP)
Date: 12-05-2014
DOI: 10.1017/S2040174414000245
Abstract: Uteroplacental insufficiency resulting in intrauterine growth restriction has been associated with the development of cardiovascular disease, coronary heart disease and increased blood pressure, particularly in males. The molecular mechanisms that result in the programming of these phenotypes are not clear. This study investigated the expression of cardiac JAK/STAT signalling genes in growth restricted offspring born small due to uteroplacental insufficiency. Bilateral uterine vessel ligation was performed on day 18 of pregnancy to induce growth restriction (Restricted) or sham surgery (Control). Cardiac tissue at embryonic day (E) 20, postnatal day (PN) 1, PN7 and PN35 in male and female Wistar (WKY) rats ( n =7–10 per group per age) was isolated and mRNA extracted. In the heart, there was an effect of age for males for all genes examined there was a decrease in expression after PN1. With females, JAK2 expression was significantly reduced after E20, while PI3K in females was increased at E30 and PN35. Further, mRNA expression was significantly altered in JAK/STAT signalling targets in Restricteds in a sex-specific manner. Compared with Controls, in males, JAK2 and STAT3 were significantly reduced in the Restricted, while in females SOCS3 was significantly increased and PI3K significantly decreased in the Restricted offspring. Finally, there were specific differences in the levels of gene expression within the JAK/STAT pathway when comparing males to females. Thus, growth restriction alters specific targets in the JAK/STAT signalling pathway, with altered JAK2 and STAT3 potentially contributing to the increased risk of cardiovascular disease in the growth restricted males.
Publisher: Wiley
Date: 31-07-2018
DOI: 10.1113/EP086846
Publisher: American Physiological Society
Date: 06-2010
DOI: 10.1152/JAPPLPHYSIOL.00127.2010
Abstract: High doses of the antioxidant vitamin C prevent the increases in skeletal muscle mitochondrial biogenesis after exercise training. Since exercise training effects rely on the acute stimulus of each exercise bout, we examined whether vitamin C supplementation also attenuates the increases in skeletal muscle metabolic signaling and mitochondrial biogenesis in response to an acute exercise bout. Male Sprague-Dawley rats performed 60 min of treadmill running (27 m/min, 5% grade) or remained sedentary. For 7 days before this, one-half of the rats received water containing 500 mg/kg body wt vitamin C. Acute exercise significantly ( P 0.05) increased the phosphorylation of p38 MAPK, AMP-activated kinase-α, and activating transcription factor (ATF)-2 and the ratio of oxidized to total glutathione (GSSG/TGSH) in the gastrocnemius. However, vitamin C had no effect on these increases. Similarly, vitamin C did not prevent the exercise-induced increases in peroxisome proliferator-activated receptor-γ coactivator-1α, nuclear respiratory factor (NRF)-1, NRF-2, mitochondrial transcription factor A, glutathione peroxidase-1, MnSOD, extracellular SOD, or glucose transporter 4 ( P 0.05) mRNA after exercise. Surprisingly, vitamin C supplementation significantly increased the basal levels of GSSG/TGSH, NRF-1, and NRF-2 mRNA and basal ATF-2 phosphorylation. In summary, despite other studies in rats showing that vitamin C supplementation prevents increases in skeletal muscle mitochondrial biogenesis and antioxidant enzymes with exercise training, vitamin C had no affect on the acute exercise-induced increases of these markers.
Publisher: American Physiological Society
Date: 10-2023
Publisher: Cold Spring Harbor Laboratory
Date: 06-08-2020
DOI: 10.1101/2020.08.04.20168542
Abstract: Testosterone is a naturally occurring hormone that has been positively associated with lean mass and strength in males. Whether endogenous testosterone is related to lean mass and strength in females is unknown. To examine the relationship between endogenous testosterone concentration and lean mass and handgrip strength in healthy, pre-menopausal females. Secondary data from the 2013-2014 National Health and Nutrition Examination Survey (NHANES)were used. Females were aged 18-40 (n=753, age 30 ± 6 yr, mean ± SD) and pre-menopausal. Multivariate linear regression models were used to examine associations between total testosterone, height-adjusted lean mass and handgrip strength. Mean ± SD testosterone concentration was 1.0 ± 0.6 nmol·L -1 and mean free androgen index (FAI) was 0.02 ± 0.02. Mean fat-free mass index (FFMI) was 16.4 ± 3.0 kg·m -2 and mean handgrip strength was 61.7 ± 10.5 kg. In females, testosterone was not associated with FFMI (β=0.08 95%CI: −0.02, 0.18 p=0.11) or handgrip strength (β=0.03 95%CI: −0.11, 0.17 p=0.67) in a statistically significant manner. Conversely, FAI was positively associated with FFMI (β=0.17 95%CI: 0.01, 0.33 p=0.04 ) but not handgrip strength (β=0.19 95%CI: −0.02, 0.21 p=0.10 ). These findings indicate that FAI, but not total testosterone, is associated with FFMI in females. The small coefficients however suggest that FAI only accounts for a minor proportion of the variance in FFMI, highlighting the complexity of the regulation of lean mass in female physiology. FAI nor total testosterone are associated with handgrip strength in females when testosterone concentrations are not altered pharmacologically.
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.FREERADBIOMED.2016.01.006
Abstract: Skeletal muscle insulin resistance and oxidative stress are characteristic metabolic disturbances in people with type 2 diabetes. Studies in insulin resistant rodents show an improvement in skeletal muscle insulin sensitivity and oxidative stress following antioxidant supplementation. We therefore investigated the potential ameliorative effects of antioxidant ascorbic acid (AA) supplementation on skeletal muscle insulin sensitivity and oxidative stress in people with type 2 diabetes. Participants with stable glucose control commenced a randomized cross-over study involving four months of AA (2 × 500 mg/day) or placebo supplementation. Insulin sensitivity was assessed using a hyperinsulinaemic, euglycaemic cl coupled with infusion of 6,6-D2 glucose. Muscle biopsies were measured for AA concentration and oxidative stress markers that included basal measures (2',7'-dichlorofluorescin [DCFH] oxidation, ratio of reduced-to-oxidized glutathione [GSH/GSSG] and F2-Isoprostanes) and insulin-stimulated measures (DCFH oxidation). Antioxidant concentrations, citrate synthase activity and protein abundances of sodium-dependent vitamin C transporter 2 (SVCT2), total Akt and phosphorylated Akt (ser473) were also measured in muscle s les. AA supplementation significantly increased insulin-mediated glucose disposal (delta rate of glucose disappearance ∆Rd) (p=0.009), peripheral insulin-sensitivity index (p=0.046), skeletal muscle AA concentration (p=0.017) and muscle SVCT2 protein expression (p=0.008) but significantly decreased skeletal muscle DCFH oxidation during hyperinsulinaemia (p=0.007) when compared with placebo. Total superoxide dismutase activity was also lower following AA supplementation when compared with placebo (p=0.006). Basal oxidative stress markers, citrate synthase activity, endogenous glucose production, HbA1C and muscle Akt expression were not significantly altered by AA supplementation. In summary, oral AA supplementation ameliorates skeletal muscle oxidative stress during hyperinsulinaemia and improves insulin-mediated glucose disposal in people with type 2 diabetes. Findings implicate AA supplementation as a potentially inexpensive, convenient, and effective adjunct therapy in the treatment of insulin resistance in people with type 2 diabetes.
Publisher: American Physiological Society
Date: 12-2023
Abstract: A National Task force of 25 Australian physiology educators used the Delphi protocol to develop seven physiology core concepts which were agreed to nationally. The aim of the current study was to unpack the 'Physiological Adaptation' core concept with the descriptor 'Organisms adjust and adapt to acute and chronic changes in the internal and external environments across the lifespan'. This core concept was unpacked by three Task force members and a facilitator into four themes and nine subthemes that encompass the role of stressors and disturbed homeostasis in adaptation, and the capacity for, and the nature of, the Physiological Adaptation. Twenty-two Task force members then provided feedback and rated the themes and subthemes for level of importance and difficulty for students to learn via an online survey using a 5-point Likert scale. Seventeen respondents completed all survey questions. For all themes/subthemes, importance was rated 1 (essential) or 2 (important n=17, means ±SD ranged from 1.1±0.3 to 2.2±0.9) and difficulty was rated 3 (moderately difficult n=17, means ranged from 2.9±0.7 to 3.4±0.9). Subtle differences in the proportion of importance scores (n=17: Fishers exact p=0.004, ANOVA F 12,220 =2.630, p=0.003 n=22: Fishers exact p=0.002, ANOVA F 12,281 =2.743, p .001), but not difficulty scores, were observed between themes/subthemes, and free-text feedback was minor. The results suggest successful unpacking of the Physiological Adaptation core concept. The themes and subthemes can inform the design of learning outcomes, assessment, and teaching and learning activities that have commonality and consistency across curricula.
Publisher: American Physiological Society
Date: 04-2020
DOI: 10.1152/AJPREGU.00260.2020
Abstract: Intrauterine growth restriction programs adult cardiorenal disease, which may be exacerbated by pregnancy and obesity. Importantly, exercise has positive cardiovascular effects. This study determined if high-fat feeding exacerbates the known adverse cardiorenal adaptations to pregnancy in rats born small and whether endurance exercise can prevent these complications. Uteroplacental insufficiency was induced by bilateral uterine vessel ligation (Restricted) or sham (Control) surgery on embryonic day 18 (E18) in Wistar-Kyoto rats. Female offspring consumed a Chow or high-fat diet (HFD) from weaning and were randomly allocated to either a sedentary (Sedentary) or an exercise protocol at 16 wk exercised before and during pregnancy (Exercise), or exercised during pregnancy only (PregEx). Systolic blood pressure was measured prepregnancy and rats were mated at 20 wk. During pregnancy, systolic blood pressure (E18) and renal function (E19) were assessed. Sedentary HFD Control females had increased estimated glomerular filtration rate (eGFR) compared with Chow. Compared with Control, Sedentary-Restricted females had increased eGFR, which was not influenced by HFD. Renal function was not affected by exercise and prepregnancy blood pressure was not altered. Restricted Chow-fed dams and dams fed a high-fat diet had a greater reduction in systolic blood pressure during late gestation, which was only prevented by Exercise. In summary, high-fat fed females born small are at a greater risk of altered cardiorenal adaptations to pregnancy. Although cardiovascular dysfunction was prevented by Exercise, renal dysfunction was not affected by exercise interventions. This study highlights that modifiable risk factors can have beneficial effects in the mother during pregnancy, which may impact fetal growth and development.
Publisher: American Physiological Society
Date: 02-2011
DOI: 10.1152/AJPREGU.00079.2010
Abstract: In sheep, central leptin infusion reduces food intake and increases energy expenditure in adipose tissue and skeletal muscle. The mechanisms for these peripheral effects of central leptin in sheep are not known but, on the basis of rodent studies, may involve AMPK. In mice, central leptin acutely increases both skeletal muscle AMPK activation and glucose uptake. Thus, to investigate whether these effects exist in higher-order mammals, ovariectomized Corriedale ewes ( n = 4 per group) received a continuous lateral ventricular infusion (60 μl/h) of either leptin (50 μg/h) or artificial cerebrospinal fluid (aCSF CON) for 8 days. Tritiated glucose (3- 3 H-glucose) was infused intravenously for calculation of whole body glucose turnover during both acute (6 h) and chronic (7–8 days) leptin/aCSF infusion. Muscle biopsies were also obtained. Leptin infusion reduced ( P 0.05) food intake and body weight, and it also increased plasma epinephrine concentration at 6 h and 7 days, suggesting increased sympathetic nerve activity. Despite this, and in contrast to rodent studies, central leptin infusion did not increase skeletal muscle AMPKα Thr 172 phosphorylation or ACCβ Ser 221 phosphorylation. Surprisingly, the glucose rate of appearance (glucose Ra) and rate of disappearance (glucose Rd) were reduced by both acute and chronic leptin infusion. Direct infusion of the AMPK activator 5-aminoimidazole-4-carboxyamide-ribonucleoside (AICAR) into the femoral artery increased skeletal muscle AMPK phosphorylation. In conclusion, although central leptin infusion in sheep caused the predicted reduction in food intake and increases plasma epinephrine concentration, it had no effect on AMPK activation in skeletal muscle and actually reduced glucose disposal. This suggests that there are species differences in the peripheral responses to central leptin infusion.
Publisher: Wiley
Date: 10-2019
DOI: 10.14814/PHY2.14216
Publisher: Wiley
Date: 09-2015
DOI: 10.14814/PHY2.12556
Publisher: Informa UK Limited
Date: 03-01-2014
No related grants have been discovered for Glenn Wadley.